In the rest of the description, “antimicrobial preservative” or “antimicrobial” is taken to mean a preservative with antimicrobial properties, i.e. a compound capable of guaranteeing protection of the ophthalmic solution from possible microbial contamination. As far as the invention is concerned such agents should be distinguished from preservative agents involved in preserving the chemical characteristics of the solution such as antioxidants e.g. EDTA.
Prostaglandins are well known active substances administered to humans or animals via the topical route in the form of ophthalmic solutions for the treatment of glaucoma. The usual dosage for these formulations is 1 drop per day in both eyes, bearing in mind that prostaglandins may also be used in combination with a second anti-glaucoma agent such as a beta-blocker, a carbonic anhydrase inhibitor or an alpha-adrenergic agonist.
The prime disadvantage of prostaglandins is that they are not water soluble, so that incorporating them into an ophthalmic solution requires a preliminary solubilization step. Moreover, another constraint on making the formulation is the requirement to provide an ophthalmic solution which is chemically stable over time, in practice for a period of between 18 and 24 months. Another characteristic required of the ophthalmic solution is that it has to be stable relative to the packaging in which it is stored, in particular relative to packaging in low-density polyethylene (LDPE) material.
Currently, most prostaglandin based ophthalmic solutions on the market contain a preservative agent which, besides having antimicrobial properties, also solubilizes the active substance and partly stabilizes it. An example of such a solution is the product marketed under the trade name of Xalatan® by Pfizer, combining latanoprost and 0.02% by weight BAC. It should be noted that, despite the presence of BAC, this ophthalmic solution is not stable at ambient temperature and must be stored in the cold at a temperature of about 5° C. Moreover, Allergan markets an ophthalmic solution under the trade name of Lumigan® combining bimatoprost and 0.005% by weight BAC.
However, the use of antimicrobial preservatives, particularly BAC, in opthalmology for long-term treatment, as is the case particularly for glaucoma, is advised against in many publications because of problems with tolerance (see in this respect: “The New Class of Ophthalmic Agents: Here's how to choose the right prostaglandin for each patient” by J. James Thimons, O.D., F.A.A.O.—Optometric Management, May issue 2002). It is thus already established that antimicrobial preservative agents are toxic in long-term use, with the result that today there is a tendency to limit their use by reducing their concentration in ophthalmic solutions as much as possible, or better still, eliminating them from formulations.
This issue has been considered in the document WO 97/29752, which discloses use in place of part of the BAC of a non-ionic agent such as Cremophor®. In the formulation proposed, the concentration of BAC is limited to 0.01% by weight, the concentration of Cremophor® EL being 0.05% by weight. A product called Travatan® is on the market combining travoprost, BAC and Creinophor®, marketed by the company Alcon, owner of the patent application WO/9729752.
Polysorbate 80 has also been used in ophthalmic solutions as a partial substitute for BAC, as is the case for the product marketed under the trade name of Rescula®, for example, by Novartis, combining unoprostone with a mixture of BAC and polysorbate 80 forming 0.015% by weight of the solution.
Documents EP 1 321 144 and EPI 666 043 describe the capacity of polysorbate 80 to slow to a greater or lesser extent the adsorption of a specific prostaglandin, tafluprost, onto polyethylene (PE), low density polyethylene (LDPE), polypropylene (PP), polyethylene terephthalate (PET) or a mix of PET/polyarylate forming the packaging. No indication is given of the possible capacity of polysorbate 80 to stabilize the solution over time for a period of 18 to 24 months. These documents contain no examples of ready-to-use ophthalmic solutions and simply state that a certain number of additives may be added to the prostaglandin and polysorbate 80 combination, for example preservatives such as BAC. Nothing in this document indicates that BAC or preservatives in general are expressly excluded from the final composition.
Document US2004/0082660 describes an ophthalmic solution without BAC containing a mixture of latanoprost and polysorbate 80 (table 1, test 2). The results given characterize the homogeneity of the solution obtained 30 minutes after 7 hours of agitation, i.e. the capacity of polysorbate 80 to solubilize latanoprost in 7 hours. No indication is given concerning the chemical stability of the solution over time.
Document EP 0850 926 describes ophthalmic solutions combining prostaglandin, polysorbate 80 and glycerine. No indication is given concerning the solubility of the prostaglandin or the chemical stability of the solution over time and relative to the packaging.